Pathologic hyperactivity is observed in several neurologic disorders including Attention Deficit Hyperactivity Disorder (ADHD) and Tourette's syndrome (TS). The general goal of this research is to understand the etiology of pathologic hyperactivity by using a well-defined animal model to identify abnormal cellular events that ultimately result in the clinical manifestation of hyperactivity. We have identified the mouse mutant coloboma as a novel animal model of hyperactivity. These mice are profoundly hyperactive with locomotor activity exceeding 3 times that of their control littermates. We have demonstrated that the hyperactivity expressed by coloboma mice is clearly the result of a deletion of the Snap gene. This gene encodes SNAP-25, a neuron-specific protein that is a component of the machinery essential for docking and holding synaptic vesicles at the presynaptic membrane in readiness for Ca 2+ triggered neurotransmitter exocytosis. Although SNAP-25 is expressed in all neurons, our experiments have focused on catecholamine (dys) regulation because catecholamines are known to regulate hyperactivity in both man and animals. We have found that defects in catecholamine regulation are specific to the striatum and nucleus accumbens; norepinephrine (NE) concentrations are significantly increased while dopamine (DA) utilization is decreased. NE and DA regulation is normal in all other brain regions. The increase in NE likely contributes to the expression of locomotor hyperactivity in these mice as depletion of NE ameliorates the coloboma mouse hyperactivity. These results provide strong evidence for the hypothesis that, in this pathologic state, NE may modulate locomotor hyperactivity. The aberrant regulation of NE in this mouse model is especially relevant, as abnormalities in NE have been identified in ADHD and TS.